title: A novel link between Slc22a18 and fat accumulation revealed by a mutation in the spontaneously hypertensive rat.
abstract: Two different strains of the spontaneously hypertensive rat (SHR) exist, either with or without a Cd36 mutation. In the F2 population derived from a cross between these two SHR strains, the mutant Cd36 allele was tightly linked to differences in metabolic phenotypes but not to those in fat pad weight. This suggested the existence of another crucial mutation related to adiposity. Linkage analysis of this F2 population showed a significant linkage between the rat chromosome 1 region (D1Rat240-D1Wox28) and fat pad weight. By integrating both positional and expression information, we identified a donor splice site mutation in the gene for solute carrier family 22 member 18 (Slc22a18) in SHR with reduced fat pad weight. This mutation was located at the linkage peak with a maximum logarithm of odds score of 7.7 and caused skipping of the whole exon 9 that results in a complete loss of a whole membrane-spanning region of the rat Slc22a18 protein. Slc22a18 mRNA was abundantly expressed in isolated adipocytes and in a differentiation-dependent manner in 3T3-L1 cells. Knockdown of the Slc22a18 mRNA via infection of adenoviral vectors markedly inhibited both triglyceride accumulation and adipocyte differentiation in 3T3-L1 cells. By contrast, overexpression of the Slc22a18 mRNA had the opposite effects. These results reveal a novel link between Slc22a18 and fat accumulation and suggest that this gene could be a new therapeutic target in obesity.
authors.affiliation: Department of Clinical and Molecular Epidemiology, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-8655, Japan; Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kozue
authors.initials: K
authors.lastname: Izumi-Yamamoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Iizuka
authors.forename: Midori
authors.initials: M
authors.lastname: Shirota
authors.forename: Miki
authors.initials: M
authors.lastname: Nagase
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Takanari
authors.initials: T
authors.lastname: Gotoda
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism*; D050154:Adiposity / Q000235:genetics*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D005223:Fats / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051379:Mice; D009154:Mutation; D009765:Obesity / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D047495:PPAR gamma / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D014280:Triglycerides / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D005223:Fats; D027701:Organic Cation Transport Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; C586303:Slc22a18 protein, rat; D014280:Triglycerides
keywords: Adipocyte differentiation; Cd36; Obesity; QTL; SHR; Solute carrier